Synthesis of Alpha-GalCer Analogues as iNKT-Cell Agonists and Reactions of 2-Methyleneoxetanes

Glycolipids, particularly a-galactosylceramides, have gained considerable attention due to their ability to modulate immune responses. The discovery of a synthetic glycolipid antigen, KRN7000, has enhanced our understanding of iNKT cell function. Since KRN7000 stimulates iNKT cells to release both Th1 and Th2 cytokines in relative amounts at which the biological activity of either one is antagonized by the other, tremendous effort has been devoted toward synthesizing analogues of KRN7000 that bias cytokine release, as such targets may offer new approaches to treating viral infections, bacterial infections, cancer, and autoimmune conditions. The first part of this proposal describes the synthesis of a series of novel carbohydrate modified analogues of a-galactosylceramide. These analogues have modifications at C6” of the sugar moiety as well as on the sphingoid base. Development of these analogues was aimed at inducing Th1 biased cytokine release in iNKT cells. For the past two decades, the Howell group has made contributions towards the novel synthesis and application of 4-membered heterocyclic compounds such as oxetanes and 2-methylene­oxetanes. The second part of this dissertation will discuss the development of Lewis acid mediated transformations utilizing 2-methyleneoxetanes to access synthetically valuable products. Herein, we present the first example of 2-methyleneoxetanes as nucleophiles in carbon-carbon bond forming reaction.